Development of a novel Virus-Like Particle vaccine-based cancer immunotherapy targeting PD-L1.

摘要 癌症免疫疗法彻底改变了当今多种癌症的治疗方法。特别是，阻止 免疫检查点蛋白的抗体，如程序性细胞死亡-1(PD-1)及其配体，程序性细胞 死亡配体1(PD-L1)，有效地释放免疫细胞对癌细胞的破坏。然而，这些产品的高昂成本 基于抗体的免疫疗法及其强化治疗方案和仅在专门医学中心可用 使目前的免疫疗法在除了最有利的社会之外的所有社会都不可行。我们假设一个有效的 疫苗可以克服基于抗体的免疫疗法的这些重大缺点，而 同时模仿它们的有效治疗益处可以影响无数更多患者的生活： 特别是，一种诱导针对肿瘤相关PD-L1蛋白的持久宿主抗体水平的疫苗将 通过抑制PD-L1：PD1免疫抑制检查点相互作用，具有强大的抗肿瘤作用。我们，在 VLP Treateutics公司开发了一种名为插入甲型病毒样的专有、即插即用的疫苗平台 粒子(I-αVLP)使用基孔肯雅(CHIK)VLP。VLP模拟本地病毒的构象，而不是病毒 基因组，因此能够刺激强大的宿主反应，而不存在安全问题。外来抗原可以被插入到 I-αVLP的表面环区。由于其独特的结构，i-αVLP可以高效地呈现240个副本的密集阵列 颗粒表面的插入抗原。I-αVLP能诱导对插入抗原的高效免疫反应，并且 Chik VLP在I期临床试验中显示出可接受的安全性。我们建议建立概念证明 我们的PD-L1靶向疫苗在三阴性乳腺癌(TNBC)样模型中的有效性，因为(1)TNBCs 在临床试验中对PD-L1/PD-1抗体疗法显示出一定的反应性；以及(2)仍有较高的 对于这种特别侵袭性的乳腺癌，对有效治疗的需求尚未得到满足，这种癌症有五种最严重的- 在所有乳腺癌中，标准化疗治疗基本上无效的患者的一年生存预后。 这项建议的目标是确定我们专有的基于I-αVLP的PD-L1疫苗接种的程度 PD-L1-α疫苗可以模拟被动PD-L1单抗治疗的效果。这项研究将提供 为将这一令人兴奋的方法推向临床试验奠定了基础。为了制造这种疫苗，我们提出了以下具体方案 目的：目的1：测定PD-L1-αVLP刺激产生与肿瘤结合的抗体的能力。 并在小鼠模型中抑制其与T细胞免疫检查点受体PD-1的结合。目标2. PD-L1-αVLP疫苗对PD-1/PD-L1抗体治疗敏感小鼠肿瘤的治疗作用 以PD-L1单抗治疗为基准的模型。目标3：确定潜在的免疫相关 我们的PD-L1-αVLP疫苗可引起包括自身免疫在内的不良反应。

Abstract Cancer immunotherapy has revolutionized today’s treatments for many forms of cancers. In particular, blocking antibodies to immune checkpoint proteins, such as programmed cell death-1 (PD-1) and its ligand, programmed cell death-ligand 1 (PD-L1), effectively unleash immune cell destruction of cancerous cells. However, the high cost of these antibody-based immunotherapies, their intensive therapeutic regimen and availability only at specialized medical centers make current immunotherapies impractical in all but the most advantaged societies. We hypothesize that an effective vaccine which can overcome these significant shortcomings of antibody-based immunotherapies while simultaneously mimicking their potent therapeutic benefits can impact the lives of countless more patients: in particular, a vaccine that induces durable levels of host antibodies against the tumor-associated PD-L1 protein will have powerful anti-tumor effects by inhibiting the PD-L1:PD1 immunosuppressive checkpoint interaction. We, at VLP Therapeutics, have developed a proprietary, ‘plug-and-play’ vaccine platform called inserted alphavirus virus-like particle (i-αVLP) using the Chikungunya (CHIK) VLP. VLPs mimic the conformation of native viruses without the viral genome, thus capable of stimulating a robust host response absent safety issues. Foreign antigens can be inserted into the surface loop domains of i-αVLP. Due to its unique structure, i-αVLP can efficiently present a dense array of 240 copies of the inserted antigen on the particle surface. i-αVLP induces highly effective immune responses to the inserted antigen, and CHIK VLPs have shown acceptable safety profiles in a Phase I clinical trial. We propose to establish proof of concept of our PD-L1-targeting vaccine’s efficacy in a triple negative breast cancer (TNBC)-like model given that (1) TNBCs have shown some responsiveness to PD-L1/PD-1 antibody therapies in clinical trials; and (2) there remains a high unmet need for effective therapies against this particularly aggressive form of breast cancer which has the worst five- year survival prognosis among all breast cancers and for which standard chemotherapy treatment is largely ineffective. The goal of this proposal is to determine the extent to which vaccination with our proprietary i-αVLP-based PD-L1 vaccine (PD-L1- αVLP) can mimic the effects of passive PD-L1 monoclonal antibody therapy. This study will provide the basis for advancing this exciting approach into clinical trials. To create this vaccine, we propose the following Specific Aims: Aim 1: Determine the ability of PD-L1-αVLP to stimulate the production of antibodies that bind to tumor- associated PD-L1 and inhibit its binding to the T-cell immune checkpoint receptor, PD-1, in murine models. Aim 2. Determine the therapeutic effects of PD-L1-αVLP vaccination in a PD-1/PD-L1 antibody therapy-sensitive murine tumor model benchmarked against PD-L1 monoclonal antibody treatment. Aim 3: Determine whether potential immune-related adverse events including autoimmunity can be induced by our PD-L1-αVLP vaccine.